Pyruvate dehydrogenase complex (PDC) deficiencies are a major class of mitochondrial diseases, limiting oxidation of carbohydrate for energy production, especially important in the brain. No definitive treatment of these disorders has been established. The proposed Natural History and Advanced Genetic Study of Pyruvate Dehydrogenase Complex Deficiencies will establish a longitudinal natural history database for PDC deficiencies, integrating our data with the NAMDC registry, creating an additional NAMDC natural history sub-database specific to PDC deficiencies, and include clinically detailed and relevant data elements that are derived from patient/family observations. We will enroll a substantial number of diverse subjects with confirmed PDC deficiencies and determine the genetic basis and pathophysiology of up to a third of PDC patients who currently have not been found to have an identified mutation in any of the primary PDC-specific genes. Our specific aims will be: 1) to establish a PDC-specific NAMDC database within the NAMDC Patient Registry, enroll 150-200 subjects through the NAMDC network, collect detailed diagnostic and clinical information with input from the subjects and their families, monitor blood tests for metabolic and treatment markers, and follow them for 3-4 years; 2) to use comprehensive advanced genetic analysis technologies (whole exome sequencing and a panel of 23 selected known genes) to find mutations in those subjects in whom none has been found, in collaboration with the NAM DC-sponsored international data exchange network (MSeqDR); and 3) to correlate these clinical and genetic findings to determine if there are different types of PDC deficiencies that may respond to different treatments, and to identify measurable clinically relevant outcomes and promising forms of treatment that could be evaluated in ongoing and future controlled clinical intervention trials.